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Acute liver failure (ALF) is a life-threatening syndrome characterised by rapid hepatocellular necrosis due to various types of insults including drugs, autoimmune disorders or viral infections, and thus represents a disease with high mortality and elevated societal costs. At present, most ALF treatment strategies are rather aimed at simply preventing complications and decelerating disease progression. Unfortunately, the only curative treatment for ALF at present is liver transplantation, an option which is limited due to financial constraints, shortage of donor livers and immunosuppression-related complications.1 Therefore, novel therapeutic avenues for patients with ALF are urgently needed.
Normally, mature hepatocytes can orchestrate liver regeneration on loss of liver mass. When severe liver insult occurs, however, hepatocytes are unable to differentiate and hepatic progenitor cells (HPCs) are activated. HPCs, embryonic stem cells (ES) and induced pluripotent stem cells (iPS) have been considered a potential source for cell replacement in the injured liver since they possess hepatic differentiation capacity.2 However, their clinical applicability remains still controversial. For long, it has been widely assumed that hepatocytes do not contribute directly to the progenitor or stem cell compartment. Recently, Chen and colleagues2 reported the dedifferentiation of progenitor cells from isolated mature hepatocytes, refuting the current dogma.
Yet to be explored was the identification of molecular cascades that specifically dedifferentiate mature hepatocytes and activate a ‘fetal programme’. The Hippo/Yes-associated protein (YAP)-signalling pathway plays an essential role by determining cellular fates in the mammalian liver. Hippo signalling controls the phosphorylation of the transcriptional co-activator YAP whose constitutive activation in …
Contributors FJC and MLM-C contributed equally in the writing of the commentary.
Funding FJC was supported by the MINECO Retos SAF2016-78711, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, ERAB Ref. EA 18/14, AMMF 2018/117 and COST Action CA17112. FJC is a Ramón y Cajal Researcher (RYC-2014-15242) and a Gilead Liver Research Scholar. MLM-C was supported by grants from NIH (US Department of Health and Human Services)-R01AR001576-11A1, Gobierno Vasco-Departamento de Salud 2013111114, ELKARTEK 2016, Departamento de Industria del Gobierno Vasco, MINECO: SAF2017–87301-R integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación 2013–2016 cofinanciado con Fondos FEDER, BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación 2013–2016 cofinanciado con Fondos FEDER and the Asociación Española contra el Cáncer. The CIC bioGUNE is a Severo Ochoa Excellence Accreditation Center (SEV-2016-0644).
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
Patient consent for publication Not required.